Co-receptor signalling is an important mechanism for coordinating and tightly regulating immune responses. The usual scheme of activation of αβ T cells relies on positive signals given by peptide antigens presented by HLA class I or II. Co-receptor signals will either increase or prevent this activation.
Among the negative signalling molecules, those belonging to CD28/B7 families are by far the most studied. Three members of this family have been described: CTL-associated antigen-4 (CTLA-4), programmed death-1 (PD-1) and B and T lymphocyte attenuator (BTLA). They all play a role in the control of tolerance. They provide negative signals that limit, terminate and/or attenuate immune responses.
BTLA (CD272) is the most recently described member of the CD28 family, it was first identified as a transcript highly specific to T helper 1 (TH1) cells but was later shown to be expressed by thymocytes. Initially, B7x was suggested as a ligand of BTLA but it has been recently confirmed that BTLA interacts with HVEM (herpes virus-entry mediator), a member of the tumour-necrosis factor receptor (TNFR) family (Gonzalez et al., Proc. Natl. Acad. Sci. USA, 2005, 102: 1116-21). The interaction of BTLA, which belongs to the CD28 family of the immunoglobulin superfamily, and HVEM, a costimulatory tumor-necrosis factor (TNF) receptor (TNFR), is quite unique in that it defines a cross talk between these two families of receptors.
BTLA is constitutively expressed in both B and T cells. Like PD-1, BTLA contains a membrane proximal immunoreceptor tyrosine-based inhibitory motif (ITIM) and membrane distal immunoreceptor tyrosine-based switch motif (ITSM). Disruption of either the ITIM or ITSM abrogated the ability of BTLA to recruit either SHP1 or SHP2, suggesting that BTLA recruits SHP1 and SHP2 in a manner distinct from PD-1 and both tyrosine motifs are required to block T cell activation.
The BTLA cytoplasmic tail also contains a third conserved tyrosine-containing motif within the cytoplasmic domain, similar in sequence to a Grb-2 recruitment site (YXN). Gavrieli et al recently showed that a phosphorylated peptide containing this BTLA N-terminal tyrosine motif can interact with GRB2 and the p85 subunit of PI3K in vitro, although the functional effects of this interaction remain unexplored in vivo (Gavrieli et al., Bioochem. Biophysi Res Commun, 2003, 312, 1236-43).
To date, no satisfactory approach has been proven to induce potent immune responses against vaccines, especially in cancer patients. Methods have yet to be devised to overcome the immunosuppressive mechanisms observed in cancer patients, and during chronic infections.